Project summary Fifty million people worldwide are living with dementia and a new case of dementia is diagnosed every 3 seconds. Dementia is a major cause of disability among older people and it has a profound health and economic impact, not only on people with dementia, but also on their caregivers, families and the larger society. Alzheimer?s disease (AD) is the main dementia afflicting 5.8 million Americans and nearly two-thirds (3.6 million) are women. Long-held view for the cause of this disparity pointed at the greater female life-span. However recent emerging evidence shows that the lifetime risk, incidence and severity of cognitive impairment and dementia are much higher among older women than in older men. This positions aging and female gender as two of the major risk factors for sporadic AD, particularly after menopause, but the biological basis of the sex-based distinctions in dementia onset and progression remain elusive. In a significant portion of the human studies the gender is regressed out and the data is pooled together to increase the effect size. Until recently, the bulk of the animal studies used only males in effort to keep the cost low by reducing the experimental groups. As a direct consequence, even though metabolic and vascular dysfunctions are now accepted to be major contributors to cognitive impairment and dementia, the sex differences for this influence are largely unknown. The goal of this project is to deliver an integrative view on sex differences in dynamic neurovascular coupling and real time neuroenergetics in rodent dementia models, particularly AD. Our central hypothesis is that vascular and metabolic dysfunctions in cognitive impairment and dementia interact with neuroendocrine regulators to drive pathology in a sex-specific manner. Our approach combines in vivo multimodal vascular and metabolic brain imaging with single cell transcriptomics to relate functional aspects of neurovascular resilience to specific cell types and uncover personalized molecular targets for therapy. We conjecture that both males and females with dementia experience decline in vascular and metabolic function that contributes to the disease etiology, however the severity, mechanism and timeline between the sexes is different. Our preliminary data in AD models shows that both sexes have decline in cerebral blood flow during the disease onset with female mice having more severe reductions and specific patters. We will measure the concomitant drop in tissue oxygenation where the with sex differences is still unclear and look for changes of glycolytic rates in the brain. We will correlate an array of vascular and metabolic measures with well described hallmarks of AD such as vascular and tissue amyloid plaques. At time points where we can observe the highest functional changes, we will use single-cell transcriptomics to look which cell types drive the neuroenergetic shifts. We aim to elucidate how the particular gene clusters sorted by the function of their protein products relate to the functional vascular and metabolic events we observe. Finally, in a prove-of-concept effort we will evaluate the therapeutic potential of pharmacogenetic and optogenetic modulation of neurons in the hypothalamus that play role in late life neurogenic hypertension. The investigation into sex differences and symptom modulation of neurodegeneration is in its infancy. Identifying the mechanisms underlying sex differences in etiology, onset and progression of Alzheimer?s disease will provide valuable insights leading to tailored therapeutics that will benefit all humans.